Aromatization

Aromatization is a chemical reaction in which an aromatic system is formed. It can also refer to the production of a new aromatic moiety in a molecule which is already aromatic. Theoretically, this can be achieved by dehydrogenation of existing cyclic compounds (such as in converting cyclohexane into benzene) or by formation of new cyclic system (such as in the cyclotrimerization of acetylene to benzene);[1] practically, other moieties are typically required to carry out such conversion, and other approaches like applying condensation reactions are possible. Aromatization includes the formation of any aromatic system (including heterocyclic systems), and is not restricted to benzene and its derivatives.

The substance now called benzene, C6H6, was known as a component of Southeast Asian aromatic resins used in perfumery since the 15th century.[2] It was first isolated and identified by Michael Faraday in 1825 who named it bicarburet of hydrogen.[3][4] In 1845, Charles Mansfield, working under August Wilhelm von Hofmann, isolated benzene from coal tar and began the industrial-scale production based on this method four years later.[5][6] Over time, consensus developed that other substances were chemically related to benzene, comprising a diverse chemical family; Hofmann used the word "aromatic" for this family for the first time in 1856.[7]

Historic benzene formulae (from left to right) by Claus (1867), Dewar (1867), Ladenburg (1869), Armstrong (1887), Thiele (1899), and Kekulé (1865). Dewar benzene and prismane are different chemicals that have Dewar's and Ladenburg's structures. Thiele and Kekulé's structures are used today.

The various representations of benzene

Historic interest in benzene arose from the uncertainty over its structure and reactivity. It was well established that it had a carbon to hydrogen ratio of 1:1 which suggested the presence of double or triple bond carbon-to-carbon bonds, yet such unsaturated compounds typically undergo addition reactions, which benzene does not. Numerous potential structures were proposed, including by Claus,[8]Dewar,[9]Ladenburg,[10]Armstrong,[11] and Thiele.[12] The most influential proposal was that of Kekulé who in 1865 suggested a cyclic structure of six carbon atoms with alternating single and double bonds[13] Kekulé based his argument on the now well-known observations of arene substitution patterns, namely that there are always only one isomer of any monoderivative of benzene and three isomers of every disubstituted derivative.[14] Critics noted that Kekulé's proposal implied that there should be two distinguishable isomers for an ortho-substitution (a 1,2-disubstituion) depending on whether a single or double bond joined these two carbons. Kekulé suggested in reply that benzene had two complementary structures and that these forms rapidly interconverted, which would also explain the lack of addition reactions (as the valency of each carbon atom is not that expected of a double bond). Though this interconversion is incorrect —in fact, they are both resonance contributors to the actual structure (which is closest to Thiele's structure)— the geometry and structure proposed by Kekulé are correct. Benzene is the prototypical example of an aromatic compound, a hitherto unknown class of compounds, and its synthesis was the first example of aromatization, the process and chemical reactions whereby an aromatic system is formed. The new understanding of benzene and all aromatic compounds was so important for both pure and applied chemistry that in 1890 the German Chemical Society organized an elaborate appreciation in Kekulé's honor, celebrating the twenty-fifth anniversary of his first benzene paper;[15] its 150th anniversary was also marked.[16] The cyclic nature of benzene was confirmed crystallographically by Kathleen Lonsdale in 1929.[17][18]

X-ray diffraction confirms that all six carbon-carbon bonds in benzene are the same length, 140 pm (1.40 Å) – intermediate between the bond lengths of single (154 pm) and double (134 pm) carbon-carbon bonds.[19] This is consistent with delocalization of the electrons from the double bonds in Kekulé's structures equally between each of the six carbon atoms which form a planar ring.[20] The molecular orbital theory description involves the formation of three delocalized π orbitals spanning all six carbon atoms, while the valence bond theory description involves a superposition of resonance structures.[21][22] This electronic structure provides benzene with unusual stability and contributes to the molecular and chemical properties which are now known as aromaticity. To accurately reflect the nature of the bonding as having neither single nor double bonds, but rather something in between, benzene is often depicted with a circle inside a hexagonal arrangement of carbon atoms, similar to the structure first illustrated by Thiele.[12]

In organic chemistry, the term aromaticity has come to refer to cyclic (ring-shaped), planar (flat) organic compounds with a ring of resonance bonds that exhibit unusually high stability relative to other geometric or connective arrangements with the same set of atoms.[24] Aromatic molecules consequently do not easily break apart and react with other substances (they have low chemical reactivity) and exhibit special physical characteristics such as π stacking[25][26] (the understanding of which is still the subject of ongoing investigation[27]). In terms of electronic structure, aromaticity describes a conjugated system made of alternating notionally single and double bonds, plus in some cases a lone pair from an occupied p-orbital perpendicular to the plane of the ring. The term "aromatic sextet" for the electronic system which resists disruption (and hence possesses unusual stability) is attributed to Sir Robert Robinson[28] though the idea can be traced further to Crocker[29] and Armstrong.[30] This configuration allows for the delocalization of π electrons around the ring, increasing the molecule's stability. Such molecules cannot be accurately represented by a single structure and are understood to exist as a combination of resonance hybrids, though single representations are frequently chosen as a short-hand for convenience. As an example, the cyclohexatriene structures Kekulé proposed should have alternating single and double bonds of different lengths, yet each is the same and has a length consistent with benzene having six "one-and-a-half" bonds which is logically the superposition of each resonance contributor.[19] A more accurate representation of the electrons following the merging of p orbitals into π-bonds (see illustration above) is Armstrong's inner cycle model as the electron density is evenly distributed around the aromatic ring[11] in molecular orbitals considered to have π symmetry,[31] though this representation is inconvenient in arrow pushing in mechanistic organic chemistry. The quantum mechanical origins of aromaticity were first modelled by Hückel in 1931.[32][33][34]

Systems following Hückel's rule, having 4n + 2 π-electrons, are aromatic, but if there are 4n π-electrons along with characteristics 1–3 above, the molecule is said to be antiaromatic. Antiaromatic systems are destabilized and sometimes adopt distorted structures to avoid planarity. An atom in an aromatic system can have other electrons that are not part of the system, and are therefore ignored for the 4n + 2 rule. For example, in furan, the oxygen atom is sp2 hybridized. One lone pair (in the pz orbital) contributes to the π system and the other in the plane of the ring (in the non-bonding sp2 orbital and analogous to the C–H bond in the other positions) does not; consequently, there are 6 π-electrons in furan and it is aromatic. Comparing the nitrogen heterocycles pyrrole and pyridine, each has a 6 π-electron system: the lone pair on the nitrogen atom is required to complete the aromatic sextet in the case of pyrrole while the lone pair of in pyridine is not required. The difference can be seen in the basicity of the two systems, as pyridine can be easily protonated (its lone pair is available for reaction) whilst pyrrole does not react readily.[36] This can be seen in the pKa values of the respective conjugate acids – 8.25 for pyridine compared with −0.27 for pyrrole.[37] In the case of oxazole and isoxazole, the lone pairs contributed to the aromatic sextet come from the occupied pz orbital of oxygen atom rather than the nitrogen lone pairs in hybridized sp2 orbitals. Electrostatic potential surfaces illustrate the difference in electronegativity of the heteroatom bearing an electron pair depending on whether or not it forms part of the aromatic system. In the diagram below, the nitrogen atom in pyridine is markedly more electronegative than nitrogen atom in indole, as indicated by the red regions on the surfaces, because the pyridine nitrogen is free to act as a Lewis base whereas the indole nitrogen is not. The surfaces also illustrate that heteroatoms influence the ability to form cation–pi interactions as cations will be attracted to the aromatic system much more strongly in indole and in benzene than will be the case in pyridine where a direct interaction with the lone pair is more favoured.[38]

Electrostatic potential surfaces for indole, benzene, and pyridine (left to right), available from the Spartan software suite of computational chemistry tools. Shading colors vary from blue (electropositive areas) to red (electronegative areas) and are determined by calculating the energy of interaction of a positive spherical point charge (a proton) as it moves over the surface of the molecule.

An aromatic ring current (orange) interacts with an applied magnetic field, B0 (red arrow) and induces a magnetic field (purple) which changes the chemical shifts in NMR experiments

Molecules which can possess an aromatic system will tend to undergo any electronic or conformational structure changes needed to attain aromaticity. Chemical changes which occur as a consequence include a tendency to undergo electrophilic aromatic substitution and nucleophilic aromatic substitution reactions, but not electrophilic addition reactions as happens with carbon–carbon double bonds.[39] This chemical behaviour offers one way to confirm experimentally that an aromatic system is present. The nuclear magnetic resonance (NMR) phenomenon offers a spectroscopic method for demonstrating and investigating aromatic systems as the circulating π-electrons produce ring currents which oppose the applied magnetic field and lead to changes in the measured chemical shifts for both 1H and 13C nuclei.[40][41]X-ray crystal structures confirm the existence of π-π interactions in aromatic systems, such as the dimer of benzene; Perpendicular and offset parallel configurations can be observed in the crystal structures of many simple aromatic compounds.[25][42] More recently, direct measures of electron delocalization allows direct quantification of the extent of aromaticity.[43]

Research work undertaken to understand the benzene system opened a new field in organic chemistry leading to the modern understanding of aromatic systems as common throughout the chemical world. Benzene itself is a useful solvent as well as a gasoline additive due to its high octane number and ability to reduce engine knocking, although methylbenzene is now being used as an alternative. Benzene is also a precursor used in the manufacture of styrene, nylon, and epoxy resins. Naphthalene is the active ingredient in traditional mothballs and is used to make the insecticide carbaryl. Aromatic systems appear in many other important industrial products including Bakelite, polystyrene, and PET plastics.[39]

(Left): A segment of DNA with nucleobase pairs π-stacked through the center of the double helix.(Center):Intercalation distorts the DNA structure by inserting suitable extended aromatic systems between base pairs. Ethidium bromide is shown along with an example of its intercalation.(Right): Tobacco smoke carcinogen and mutagen[71]benzo[a]pyrene metabolises to (+)-Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide which reacts with a guanine base and intercalates the pyrene system between nucleobases.

If three alkyne moieties are tethered together, it is possible to create three rings in a single step without the problems with side products mentioned above. An example is seen in the synthesis of calomelanolactone using Wilkinson's catalyst to achieve an intramolecular cyclotrimerization.[79]

The Bergman cyclization is conceptually similar, using a enediyne with (Z)-stereochemistry plus a hydrogen donor, catalysed by metal centre like ruthenium;[80] (Z)-hex-3-en-1,5-diyne cyclizes to benzene after reduction of the intermediate diradical, for example.[81] The enediyne moiety can be included within an existing ring, allowing access to a bicyclic system under mild conditions as a consequence of the ring strain in the reactant. Cyclodeca-3-en-1,5-diyne reacts with 1,3-cyclohexadiene to produce benzene and tetralin at 37 °C, the reaction being highly favorable owing to the formation of two new aromatic rings:

Another effective means of generating heterocyclic systems is to effect ring-closure using the heteroatom. "Moderately aromatic" arsole derivatives can be formed by dimerising diphenylacetylene with lithium to form 1,4-dilithiotetraphenyl-1,3-butadiene.[96] Phenylarsenous dichloride is added to close the ring to form pentaphenylarsole.[97] The diiodo analogue of the lithium salt can be used in its place, and other pnictogen heterocycles can be produced by replacing the arsenic compound as appropriate.

The 10 π-electron system cyclodecapentaene is non-aromatic as it is non-planar, but aromatic derivatives can be prepared. In the following reaction sequence, naphthalene is converted through a series of non-aromatic intermediates to 1,6-methano[10]annulene by Birch reduction, carbene addition, and then DDQ oxidation.[101] Many other conversions of one aromatic system to another are known. One simple example is the industrial synthesis of pyrrole by exchanging the oxygen atom in furan for a nitrogen moiety. Ammonia and solid acid catalysts (like SiO2 and Al2O3) are required.[102] Pyrrole can be converted to 3-chloropyridine by insertion of a carbene into the five-member ring. Dichlorocarbene adds to form a strained bicyclic cyclopropane system which then opens to form the six-member pyridine product, a transformation known as the Ciamician-Dennstedt rearrangement.[103]

Corannulene, a [5]circulene, is a fragment of buckminsterfullerene which is found in the buckycatcher shown above and often called a buckybowl due to its bowl-like shape. Motivation for its synthesis was the hypothesis that it would display annulene-within-an-annulene aromaticity, with a 6 π-electron cyclopentadienyl anion core within a 14 π-electron annulenyl cation.[118] Later work has questioned the validity of this model though the molecule is definitely aromatic.[119][120] The dianion has been demonstrated to be antiaromatic and the tetraanion is aromatic.

An isomerization reaction involves the rearrangement of atoms within a single molecule to one of its isomers. Some isomerization processes may occur spontaneously, resulting in an equilibrium between the isomers, and the position of the system generally favors an aromatic product if the process is itself an aromatization. Amongst keto-enol tautomers, the keto form is generally favoured on by thermodynamics, but in the case of cyclohexa-2,4-dienone its aromatic isomer phenol is strongly favoured.[126] The equilibrium constant for this system has been determined to be 10−13, meaning that in phenol there are 10 trillion molecules in the aromatic enol form for every molecule in the keto form.[127] Isomerization reactions are temperature dependent, for example melting 1,4-naphthalenediol at 200 °C produces a 2:1 mixture with its keto form, 1,4-dioxotetralin.[128] The conversion to the 1,4-dioxotetralin tautomer can be driven to completion when bound in a chromium tricarbonyl piano stool complex.

A non-tautomeric example of isomerization can be seen in the azulene–napthalene system, a thermal rearrangement[129] in which each of the compounds is stable at room temperature; such interconversion aromatization reactions are rare.[130]Carbon-13 isotope studies have shown scrambling of the α- and β- positions of naphthalene through an azulene intermediate at elevated temperatures[131] though naphthalene has roughly double the aromatic stabilization of azulene. The synthesis of the azulene system is an example of a multi-step organic synthesis, in this case from cycloheptatriene, as shown below.[132] Azulene is unusual in that it is a polar hydrocarbon – the molecular dipole moment of azulene is 1.08 D compared with naphthalene's 0 D.[133] This can be understood by recognizing that one of the important resonance contributors for azulene has the tropylium cation fused to the cyclopentadienyl anion; reactivity studies confirm the electrophilic and nucleophilic characteristics of these rings, respectively.